ABSTRACT/SUMMARY The polymorphic fungus, Candida albicans is part of the endogenous human mycobiota. It colonizes mucosal surfaces of 30-70% of healthy individuals. The fungus causes both superficial mucosal diseases and life threatening invasive infection. Oropharyngeal candidiasis (OPC) causes significant morbidity in a large and diverse population of patients, including those with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, cancer of the head and neck, or the use of steroids Nearly 10 million cases of HIV/AIDS associated OPC occur annually and nearly one fifth of these cases have esophageal involvement. To cause OPC, C. albicans must adhere to and invade the oral mucosa, and resist being killed by host phagocytes. Dr. Swidergall discovered that EphA2 on oral epithelial cells and neutrophils is a novel pattern recognition receptor for C. albicans. EphA2 binds exposed ?-glucan on the fungal cell walls, and the preliminary data indicate that it plays a key role in the response of both epithelial cells and neutrophils to the organism. The central objective of this proposal is to determine how the ?-glucan receptor EphA2 interacts with other host signaling molecules to induce an inflammatory response in both the oral mucosa and leukocytes, and induce oral epithelial cell invasion during OPC. Aim 1 will evaluate the role of EphA2 activation and downstream signaling in oral epithelial cells during oral C. albicans infection in vitro and in vivo. Aim 2 will characterize the mechanisms by which EphA2 activation triggers neutrophil fungicidal activity. The long-term goal of this research is to determine how host receptors recognize invading fungi and maintain mucosal immunity so that new drugs and strategies to treat and prevent fungal diseases can be developed. The candidate, Dr. Swidergall, has a longstanding interest in mycology research. After completing the mentored phase of this K99, his goal is to become an assistant professor at a leading academic research institute, where he plans to continue his research on the role of critical host cell receptors in the pathogenesis of OPC. He also plans to teach students and train future scientists. This K99/R00 proposal is designed to complement Dr. Swidergall's prior research training and provide him with the necessary technical and intellectual expertise to become an independent investigator. The training he will receive in the K99 phase will substantially enhance his career prospects, and make him highly competitive for faculty positions in top research institutes. Dr. Swidergall's primary mentor, Dr. Scott G. Filler, and co-mentor, Dr. Michail S. Lionakis, were carefully selected for their relevant, diverse, and complementary expertise to cover all elements of his proposal. In addition, Dr. Swidergall has assembled an advisory committee of a diverse group of scientists to oversee his scientific progression and career development during his transition to an independent investigator. All members of this committee are senior scientists with extensive experience in mentoring postdocs.